Chronic occupational exposure to arsenic induces carcinogenic gene signaling networks and neoplastic transformation in human lung epithelial cells

Details

• Personal Author:
  Barnett JB ; Davis ME ; Holaskova I ; Jiang B-H ; Lu Y ; Rojanasakul Y ; Schafer R ; Stueckle, Todd A. ; Wang L
• Description:
  Chronic arsenic exposure remains a human health risk; however a clear mode of action to understand gene signaling-driven arsenic carcinogenesis is currently lacking. This study chronically exposed human lung epithelial BEAS-2B cells to low-dose arsenic trioxide to elucidate cancer promoting gene signaling networks associated with arsenic-transformed (B-As) cells. Following a 6month exposure, exposed cells were assessed for enhanced cell proliferation, colony formation, invasion ability and in vivo tumor formation compared to control cell lines. Collected mRNA was subjected to whole genome expression microarray profiling followed by in silico Ingenuity Pathway Analysis (IPA) to identify lung carcinogenesis modes of action. B-As cells displayed significant increases in proliferation, colony formation and invasion ability compared to BEAS-2B cells. B-As injections into nude mice resulted in development of primary and secondary metastatic tumors. Arsenic exposure resulted in widespread up-regulation of genes associated with mitochondrial metabolism and increased reactive oxygen species protection suggesting mitochondrial dysfunction. Carcinogenic initiation via reactive oxygen species and epigenetic mechanisms was further supported by altered DNA repair, histone, and ROS-sensitive signaling. NF-?B, MAPK and NCOR1 signaling disrupted PPAR?/?-mediated lipid homeostasis. A 'pro-cancer' gene signaling network identified increased survival, proliferation, inflammation, metabolism, anti-apoptosis and mobility signaling. IPA-ranked signaling networks identified altered p21, EF1?, Akt, MAPK, and NF-?B signaling networks promoting genetic disorder, altered cell cycle, cancer and changes in nucleic acid and energy metabolism. In conclusion, transformed B-As cells with their whole genome expression profile provide an in vitro arsenic model for future lung cancer signaling research and data for chronic arsenic exposure risk assessment. [Description provided by NIOSH]
• Subjects:
  Arsenic Carcinogens Genetics Inorganic Chemicals Lung Lung Diseases Neoplasms Occupational Health Respiratory System Respiratory Tract Diseases Safety

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• Keywords:
  Arsenic-compounds Author Keywords: Arsenic Cancer Carcinogenesis Exposure-levels Genes Global Gene Expression Ingenuity Pathway Analysis Lung-cells Lung Cancer
• ISSN:
  0041-008X
• Document Type:
  Text
• Genre:
  Journal Article
• Place as Subject:
  OSHA Region 3 ; Pennsylvania ; West Virginia
• CIO:
  National Institute for Occupational Safety and Health (NIOSH)
• Division:
  HELD - Health Effects Laboratory Division
• Topic:
  Workplace Safety & Health
• Location:
  North America
• Pages in Document:
  204-216
• Volume:
  261
• Issue:
  2
• NIOSHTIC Number:
  nn:20040762
• Citation:
  Toxicol Appl Pharmacol 2012 Jun; 261(2):204-216
• Contact Point Address:
  Yon Rojanasakul, PO Box 9530, Department of Basic Pharmaceutical Sciences, West Virginia University, Morgantown,WV 26506
• Email:
  yrojan@hsc.wvu.edu
• CAS Registry Number:
  Arsenic (CAS RN 7440-38-2) ; Arsenic trioxide (CAS RN 1327-53-3)
• Federal Fiscal Year:
  2012
• NORA Priority Area:
  Manufacturing
• Peer Reviewed:
  True
• Source Full Name:
  Toxicology and Applied Pharmacology
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:8f578290e11d3be98e9516c63d17652169fe84a377031f36da76088aa2752b477fa9d5cb64b0dd90f80292a6a9767a93bbfcd0892880eef58259bbad248c90af
• Download URL:
  https://stacks.cdc.gov/view/cdc/193515/cdc_193515_DS1.pdf
• File Type:
  [PDF - 1.55 MB ]